Heterogeneous Heparin Presentation in Microporous Annealed Particle (MAP) Hydrogel for Accelerated Biomaterial-Tissue Integration

Regenerative biomaterials seek to restore function and structure to a damaged tissue; however, translation of regenerative biomaterials into the clinic has been limited by negative foreign body responses that restrict tissue ingrowth. Avoiding a foreign body response while promoting active tissue ingrowth could be the foundational features needed to enable biomaterial clinical translation.

Recently, a new class of biomaterial called microporous annealed particle (MAP) hydrogel has shown great promise for clinical translation as it avoids the traditional foreign body response associated with biomaterial implants. MAP hydrogels are composed of an injectable slurry of highly concentrated, micron-scale hydrogel particles that are covalently linked together post-injection to form a stable porous structure that facilitates immediate cellular ingrowth. While MAP hydrogel was originally composed of relatively bioinert and homogeneous poly(ethylene glycol) hydrogel particles, this dissertation was focused on adding heterogeneous bioactivity to the MAP hydrogel platform to accelerate biomaterial-tissue integration.

In tissues, the extracellular matrix dictates cellular function by providing a physical support for cell growth, in addition to serving as a heterogeneous reservoir of growth factors. Scaffold-mediated delivery of exogenous growth factors, which are key regulators of tissue behavior, is a common strategy to promote tissue ingrowth. However, the translation of growth factor-releasing scaffolds to the clinic poses several hurdles, including a lengthier FDA approval, difficult storage conditions, increased costs, and the potential for dangerous off-target side effects. Additionally, these bioactive cues are heterogeneously presented and constantly changing in tissues; therefore, the spatiotemporal presentation of these cues is important to consider when designing bioactive scaffolds to promote tissue ingrowth. While patterning growth factors has been extensively explored to recapitulate the spatiotemporal presentation of cues occurring in vivo, these patterning approaches often require advanced ex vivo fabrication strategies (e.g., photopatterning, 3D printing) that limit injectability and the ability to fill large tissue defects.

To change paradigms and harness the local, endogenous growth factors produced during a body’s response to injury (e.g., wounds or biomaterial implantation), we chose to incorporate heparin heterogeneously into our MAP hydrogels using a strategy we have termed heparin microislands. Heparin electrostatically sequesters growth factors naturally, which is a quality we have recapitulated in our heparin modified MAP particles. By immobilizing heparin in a small subset of our hydrogel particle population, we demonstrate an ability to easily create a controlled heterogeneous and instructive environment through simple mixing of different particle populations while maintaining injectability.

We explored the ability of heparin microislands to accelerate tissue integration in challenging microenvironments using two clinical applications: vocal fold augmentation and diabetic wound healing. These particular applications pose unique challenges, including the promotion and maintenance of long-term implant stability and function in the dynamic vocal fold tissue and the promotion of healing in the highly inflammatory, pathologically poorly healing diabetic wound environment. In addition, we demonstrate the potential of heparin microislands for controlled growth factor release to enhance wound healing and computational optimization of the ratio of heparin microislands to promote angiogenesis.

In this dissertation we present an advancement upon a promising biomaterial platform by adding a robust and simple bioactive component for heterogeneous local growth factor sequestration. We believe this will provide an inexpensive, easy-to-translate, bioactive scaffold for enhanced tissue-biomaterial integration that can be repurposed for numerous regenerative medicine applications beyond those presented in this dissertation.